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A NAFLD Model Created By Endoplasmic Reticulum Stress Response-Associated Steatosis in Human Induced Pluripotent Stem Cell-Derived Hepatocytes

ABSTRACT: Our study reports a phenotypic approach to model hepatic steatosis in induced pluripotent stem cell-derived hepatocytes

ORGANISM(S): Homo sapiens

PROVIDER: GSE116185 | GEO | 2018/09/13

REPOSITORIES: GEO

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A NAFLD Model Created By Endoplasmic Reticulum Stress Response-Associated Steatosis in Human Induced Pluripotent Stem Cell-Derived Hepatocytes

Project description:A NAFLD Model Created By Endoplasmic Reticulum Stress Response-Associated Steatosis in Human Induced Pluripotent Stem Cell-Derived Hepatocytes

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A nonalcoholic fatty liver disease model in human induced pluripotent stem cell-derived hepatocytes, created by endoplasmic reticulum stress-induced steatosis.

Project description:Hepatic steatosis, a reversible state of metabolic dysregulation, can promote the onset of nonalcoholic steatohepatitis (NASH), and its transition is thought to be critical in disease evolution. The association between endoplasmic reticulum (ER) stress response and hepatocyte metabolism disorders prompted us to characterize ER stress-induced hepatic metabolic dysfunction in human induced pluripotent stem cell-derived hepatocytes (hiPSC-Hep), to explore regulatory pathways and validate a phenotypic in vitro model for progression of liver steatosis. We treated hiPSC-Hep with a ratio of unsaturated and saturated fatty acids in the presence of an inducer of ER stress to synergistically promote triglyceride accumulation and dysregulate lipid metabolism. We monitored lipid accumulation by high-content imaging and measured gene regulation by RNA sequencing and reverse transcription quantitative PCR analyses. Our results show that ER stress potentiated intracellular lipid accumulation by 5-fold in hiPSC-Hep in the absence of apoptosis. Transcriptome pathway analysis identified ER stress pathways as the most significantly dysregulated of all pathways affected. Obeticholic acid dose dependently inhibited lipid accumulation and modulated gene expression downstream of the farnesoid X receptor. We were able to identify modulation of hepatic markers and gene pathways known to be involved in steatosis and nonalcoholic fatty liver disease (NAFLD), in support of a hiPSC-Hep disease model that is relevant to clinical data for human NASH. Our results show that the model can serve as a translational discovery platform for the understanding of molecular pathways involved in NAFLD, and can facilitate the identification of novel therapeutic molecules based on high-throughput screening strategies.

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Lack of de novo phosphatidylinositol synthesis leads to endoplasmic reticulum stress and hepatic steatosis in cdipt-deficient zebrafish

Project description:cdipt is an essential gene in the synthesis of phosphatidylinositol (PtdIns) in the zebrafish, Danio rerio. The zebrafish mutant cdipt^hi559Tg (ZL782) carries a retroviral insertion which inactivates cdipt. Homozygous mutants exhibit hepatocellular endoplasmic reticulum (ER) stress and non-alcoholic fatty liver disease (NAFLD) pathologies at 5 days post fertilization (dpf). This study reveals a novel link between PtdIns, ER stress, and steatosis. We compared whole animal gene expression profiles of hi559 mutant larvae with phenotypically wild type larvae from a heterozygote incross in triplicate.

2011-05-09 | E-GEOD-17711 | biostudies-arrayexpress

Transcriptomic analysis of endoplasmic reticulum stress (ERS) regulated genes in mouse primary hepatocytes.

Project description:Mouse primary hepatocytes (MPH) prepared from C57Bl6 male adult mice were treated with the ERS-drug thapsigargin and used to prepare RNA.

2020-04-29 | GSE122507 | GEO

Lack of de novo phosphatidylinositol synthesis leads to endoplasmic reticulum stress and hepatic steatosis in cdipt-deficient zebrafish

2011-05-09 | GSE17711 | GEO

ChIP-seq analysis of changes in H3K27ac by endoplasmic reticulum stress (ERS) in mouse primary hepatocytes.

Project description:Mouse primary hepatocytes (MPH) prepared from C57Bl6 male adult mice were treated with the ERS-drug thapsigargin and ChIP-seq was performed using an H3K27ac antibody (Active Motif ref 39685).

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Hepatocytes cyclooxygenase-2 deficiency improves liver injury via inhibition of endoplasmic reticulum stress and epithelial-mesenchymal transition

Project description:The mechanism underlying the loss of normal liver tissues in liver cirrhosis, mainly hepatocytes, is not well-characterized. Endoplasmic reticulum (ER) stress-induced cell death has emerged as a potential mechanism for chronic liver diseases. We have previously demonstrated that cyclooxygenase-2 (COX-2) is closely related to the progress of liver cirrhosis. In this study, we aimed to verify whether hepatocytes COX-2 deficiency could protect liver injury via inducing ER stress in liver cirrhosis.

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Prolonged Endoplasmic Reticulum-Stressed Hepatocytes Drive an Alternative Macrophage Polarization.

Project description:Relatively little is known about the effects of hepatocytes on hepatic macrophages, particularly under the situation of endoplasmic reticulum (ER) stress. We examined the effects of hepatocytes conditioned media (CM) from HepG2 treated with ER stress inducers, tunicamycin or thapsigargin, on the secretion of cytokines, expression of ER stress markers, and polarization of phorbol myristate acetate-activated THP-1 cells (pTHP-1). We found that CM decreased the production of the proinflammatory cytokines including tumor necrosis factor ?, interleukin 6 (IL-6), and IL-1? as well as other cytokines and chemokines from pTHP-1 cells. These effects are mediated by the inhibition of TLR4 expression and nuclear factor ?B signaling pathway. In addition, hepatocytes CM increased the expression of binding immunoglobulin protein and the transcription factor C/EBP homologous protein (CHOP) in pTHP-1 cells. Preconditioning with ER stress inhibitor, small molecular chaperone 4-phenylbutyrate before addition of ER stressors, attenuated the ER stress in macrophages, the property of hepatocytes CM to alter tumor necrosis factor ? production and nuclear factor ?B expression by macrophages. Remarkably, treatment of macrophage with these CM leads to an alternative activation of macrophages mediated by peroxisome proliferator-activated receptor ? signaling pathway, which might be resulted from the secretion of IL-10 and IL-4 as well as releasing apoptotic bodies from hepatocytes under ER stress. Our results highlight a mechanism of ER stress transmission from hepatocytes to macrophage that drives an alternative activation of macrophages, which depends on the exposure of hepatocytes to severe and prolonged ER stress.

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Alcohol disrupts endoplasmic reticulum function and protein secretion in hepatocytes.

Project description:Many alcoholic patients have serum protein deficiency that contributes to their systemic problems. The unfolded protein response (UPR) is induced in response to disequilibrium in the protein folding capability of the endoplasmic reticulum (ER) and is implicated in hepatocyte lipid accumulation and apoptosis, which are associated with alcoholic liver disease (ALD). We investigated whether alcohol affects ER structure, function, and UPR activation in hepatocytes in vitro and in vivo.HepG2 cells expressing human cytochrome P450 2E1 and mouse alcohol dehydrogenase (VL-17A) were treated for up to 48 hours with 50 and 100 mM ethanol. Zebrafish larvae at 4 days postfertilization were exposed to 350 mM ethanol for 32 hours. ER morphology was visualized by fluorescence in cells and transmission electron microscopy in zebrafish. UPR target gene activation was assessed using quantitative PCR, in situ hybridization, and Western blotting. Mobility of the major ER chaperone, BIP, was monitored in cells by fluorescence recovery after photobleaching (FRAP).VL-17A cells metabolized alcohol yet only had slight activation of some UPR target genes following ethanol treatment. However, ER fragmentation, crowding, and accumulation of unfolded proteins as detected by immunofluorescence and FRAP demonstrate that alcohol induced some ER dysfunction despite the lack of UPR activation. Zebrafish treated with alcohol, however, showed modest ER dilation, and several UPR targets were significantly induced.Ethanol metabolism directly impairs ER structure and function in hepatocytes. Zebrafish are a novel in vivo system for studying ALD.

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Real-time quantitative PCR miRNA analysis of human hepatocytes

Project description:Primary human hepatocytes were treated with compounds modulating steatosis: palmitic acid, compound C and metformin qPCR miRNA expression profiling. Hepatocytes were treated as indicated in the summary. Equal amount total RNA was pooled prior to miRNA expression analysis

2020-02-11 | GSE145039 | GEO

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